Atherosclerotic disease is the major cause of death and disability in much of the world. Identifying genetic[unreadable] and environmental contributions to disease susceptibility is a current challenge requiring clinical and animal[unreadable] model studies. The creation of induced mutant mouse models susceptible to atherosclerosis has heralded a[unreadable] new era of research into the genetics of this disease. Not only can candidate genes be tested directly, but[unreadable] new genes and pathways can be identified by quantitative trait locus (QTL) mapping. In crosses[unreadable] betweenC57BL/6J and FVB/N mice on the apo E knockout background, a very strong proximal chromosome[unreadable] 10 atherosclerosis susceptibility locus was identified. Unexpectedly, the genotypic means for aortic root[unreadable] lesion area for markers at this locus indicated homozygosity for the FVB/N allele was associated with[unreadable] increased atherosclerosis compared to heterozygosity and homozygosity for the C57BL/6J allele. This[unreadable] finding was confirmed by characterizing congenic lines encompassing the 0 to 21.9cM region. Now, eight[unreadable] subcongenic lines have also been characterized and it appears the locus is complex with one gene between[unreadable] 11.4 and 19.6 Mb (10a) and another between 20.0 and 22.3 Mb (10b). A promising candidate gene in the[unreadable] 10a region, named A20, has been studied. A20 is a gene turned on by the TNFa/NFkB pathway, which then[unreadable] acts to shut down signaling through the pathway. C57BL76J and FVB/N A20 were shown to differ at a single[unreadable] codon and after TNFa stimulation FVB/N A20 was much more effective at shutting down the TNFa/NFkB[unreadable] pathway than C57BL/6J A20. The TNFa/NFkB pathway is both proinflammatory and antiapoptotic and could[unreadable] influence atherosclerosis by either mechanism. The specific aims of this proposal are to identify the causal[unreadable] genes in the 10a and 10b regions by further defining the critical intervals with additional subcongenic lines,[unreadable] sequencing and expression analysis of genes within these intervals, and the creation of induced mutant[unreadable] mouse lines for promising genes to prove causation. In addition, the role of A20 in atherosclerosis will be[unreadable] further explored in induced mutant mice and mechanistic studies will be carried out in whole animal and[unreadable] tissue culture studies. Particular attention will be paid to how the functional difference between C57BL/6J[unreadable] and FVBV/N A20 may act to alter the balance between TNFa mediated inflammation and apoptosis and how[unreadable] this might affect atherosclerosis progression. We anticipate that these studies will shed light on new genes[unreadable] and pathways that control atherosclerosis susceptibility, which may lead to improved diagnosis of[unreadable] susceptible individuals in the population, and someday to novel mechanism based therapies.